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Tutor

Dra. Anna Maria Costa Arnau

Departament de Química Inorgànica i Orgànica

Treball Final de Grau

Review of alternative macrocyclization methods for the synthesis of macrolides

Revisió de mètodes alternatius de macrociclació per a la síntesi de macròlids

Maria del Carmen Aznar Luque June 2018

Aquesta obra està subjecta a la llicència de: Reconeixement–NoComercial-SenseObraDerivada

http://creativecommons.org/licenses/by-nc-nd/3.0/es/

Les ciències tenen les arrels amargues, però molt dolços els fruits.

Aristòtil

Primerament, vull agrair tot el suport rebut per part de la meva tutora, la Dra. Anna Maria

Costa Arnau. Sense la teva ajuda aquest treball no hauria arribat a bon port. Gràcies per tots

els consells, les indicacions i les hores dedicades a aquest petit projecte.

També vull donar les gràcies a l’Araceli i al Sergi. Els vostres ànims m’han permès seguir

treballant com el primer dia. Gràcies per escoltar les meves inquietuds i oferir la vostra mà

sempre que l’he necessitada.

REPORT

Review of alternative macrocyclization methods for the synthesis of macrolides 1

CONTENTS

1. SUMMARY 3

2. RESUM 5

3. INTRODUCTION 7

4. OBJECTIVES 11

5. METHODS 13

6. RESULTS AND DISCUSSION 15

6.1. MACROCYCLIZATION VIA STILLE COUPLING 21

6.2. MACROCYCLIZATION VIA HECK COUPLING 24

6.3. MACROCYCLIZATION VIA SUZUKI COUPLING 28

6.4. MACROCYCLIZATION VIA WITTIG REACTION 31

6.5. MACROCYCLIZATION VIA HORNER-WADSWORTH-EMMONS REACTION 32

7. CONCLUSIONS 39

8. REFERENCES AND NOTES 41

9. ACRONYMS 47

2 Aznar Luque, Maria del Carmen


1. SUMMARY

Macrolides, macrocyclic lactones containing at least a ring of twelve members, present

many interesting features, such as antibiotic, antifungal or anticancer activities, among others.

Isolation from natural sources often provides limited quantities of these compounds. Therefore

there is great interest in the consecution of their total syntheses. A key step in their preparation

is cyclization, since it is often a challenging step. The most common method to form the ring is

macrolactonization, although, in recent years, ring-closing metathesis has also been used by

many research groups. However, these methods are not always appropriate for all macrolides,

depending on their size and structure. In this report, an exhaustive bibliographic search has

been undertaken to analyze which alternative methods are being used most often to cyclize

these compounds. SciFinder and Reaxys are the databases that have been chosen for this

search during the period 2012 to 2017. Several methods have been identified. Apart from

macrolatonizations and ring-closing metathesis, the most popular are cross-coupling methods

and olefinations. The use of the most common alternatives for the total synthesis of natural

product macrolides in the period 2012–2017 has been reviewed.

Keywords: Macrolide, Total Synthesis, Macrocyclization



2. RESUM

Els macròlids, lactones macrocícliques que contenen un mínim de dotze baules, presenten

moltes propietats interessants, com activitats antibiòtiques, antifúngiques i anticancerígenes,

entre d’altres. L’aïllament d’aquestes molècules de fonts naturals ens proporciona quantitats

molt petites d’aquests compostos. Per això hi ha molt interès en les seves síntesis totals. Un

pas clau en la seva preparació és la ciclació, ja que sovint és un pas complicat.. El mètode més

comú per formar l’anell és la macrolactonització, tot i que, en aquests darrers anys, el

tancament d’anell per metàtesi també ha estat usat per molts grups de recerca. Tot i això,

aquests mètodes no són sempre adequats per molts macròlids, depenent de la seva mida i

estructura. En aquest treball, s’ha realitzat una recerca bibliogràfica exhaustiva per trobar quins

mètodes alternatius a la macrolactonització i la metàtesi s’empren més sovint per a la ciclació

d’aquests compostos. Les bases de dades escollides per fer la cerca han estat SciFinder i

Reaxys, en el període que va del 2012 al 2017. Diversos mètodes han estat identificats. A part

de la macrolactonització i la metàtesi de tancament d’anell, els més populars són els

acoblaments creuats i les olefinacions. S’ha revisat l’ús de cinc d’aquests mètodes per a la

síntesi total de macròlids naturals en el període 2012–2017.

Paraules clau: Macròlids, Síntesi Total, Macrociclació



3. INTRODUCTION

Macrolides, macrocyclic lactones with a ring of twelve members or more,1 present a number

of interesting properties that make them especially useful in many areas.2 For example, we can

find macrolides with antibiotic, cytotoxic and antiangiogenesis properties, or having pheromone

and insecticide activities. Since the first isolation of a macrolide in the 1950s, their properties

have been investigated by many research groups, and many applications for this class of

compounds have been found, particularly in drug discovery. For instance, Erythromycin A and

its semi-synthetic analogs are used to treat bacterial respiratory infections, and Amphotericin B

is a polyene antifungal drug. Other examples are Spinosyn A and D that are used against a

wide variety of insects, and Epothilone A, an analogs of which has already been approved for

the treatment of breast cancer (Figure 1).

Figure 1. Examples of Macrolides.


Because of the minute amount of these compounds available by isolation from the natural

sources, the total synthesis of macrolides is crucial to access enough quantities to study them

further. Total synthesis of such complex molecules involves many steps and the order of these

steps is important for the success of the synthesis. One of the most important steps is the

formation of the ring, not always an easy task, although nowadays there are a wide range of

methods available for macrocyclization, such as macrolactonization, the method traditionally

used to construct the ring.

Macrolactonization2 involves the reaction of a hydroxyl and a carboxylic acid group from a

seco-acid. The activation of either the alcohol or the carboxylic acid terminal group is usually

required to achieve the reaction (Scheme 1). Depending on the group activation, we can have

different macrolactonization methods. Nowadays, some of the most commonly used methods in

the synthesis of macrolides are the Yamaguchi, Shiina or Kita–Trost procedures, if the activated

group is the acid, and the Mitsunobu protocol, if the activated group is the hydroxyl. The main

problem that macrolactonization reactions present is the competition between intramolecular

and intermolecular reactions. To solve this, the reaction is performed under high dilution

conditions: the substrate is slowly added over many hours to a large volume of solvent. Another

alternative method to avoid this situation is to immobilize the seco-acid, or an activated

intermediate, on a solid support.

Scheme 1. Cyclization by macrolactonization.

Although macrolactonization is the typical method for the construction of a macrolide ring, in

the last decade ring-closing metathesis3 has been used more and more.


Ring-closing metathesis (RCM) is a cyclization method via carbon-carbon bond formation. It

involves the reaction of two terminal alkenes (Scheme 2). The main advantage of RCM is the

compatibility with most functional groups. In addition, it generates a double bond in the molecule

that can be transformed into another functional group. However, controlling the stereochemistry

of this double bond and finding appropriate reaction conditions is not an easy task. The reaction

needs a catalyst to guarantee its success. Although the most common catalysts are ruthenium

complexes, highly reactive molybdenum Schrock catalysts are also used.

Scheme 2. Cyclization by ring-closing metathesis.

Although macrolactonization reactions and ring-closing metathesis are commonly applied to

form the ring of complex macrolides, their implementation is not always straightforward and

application to a particular substrate can be problematic and low-yielding. Taking into account

that formation of the ring is usually one of the last steps of a total synthesis, this can severely

affect its global yield. Due to our involvement in the total synthesis of several macrolides,4–8 our

group has a long-standing interest in macrocyclization reactions in general and


macrolactonizations9 in particular, a reaction which we have used regularly to form the lactone

ring of naturally-occurring macrolides synthesized in our labs. Apart from the two methods

described previously, other macrocyclization reactions are employed in the total synthesis of

macrolides, although to a lesser extent. Knowing which methods are available to form the ring of

complex macrolides and their advantages and disadvantages compared to the most standard

methodologies will help us choose the best macrocyclization strategy for a particular substrate

and streamline its total synthesis.

.


4. OBJECTIVES

Considering the interest of our research group in the total synthesis of macrolides, our main

objective is the analysis and review of alternatives to macrolactonization and RCM for the

formation of the ring of a macrolide. To achieve this, the following steps were taken:

Exhaustive review of the literature (2012–2017) using the Reaxys and SciFinder

databases.

Analysis of the results and organization of the references into tables.

Review of the literature found for five selected methods.



5. METHODS

To fulfill our objective, we first searched the literature for reports on the total synthesis of

macrolides that meet specific structural characteristics. We considered only natural-product

macrolides and excluded cyclodepsipeptides, macrodiolides and ansa-macrolides. In addition,

macrolides with a fused benzene ring were not taken into account. The search was made in the

recent literature (2012–2017) and using two chemical databases: SciFinder and Reaxys.

First, we searched using the keywords “total synthesis macrolide” on both databases. This

search was filtered by year, journal name and type of document. Moreover, we searched by

reaction using Scheme 3 as template on Reaxys. In that case, the filters that were applied are

by year, type of document and number of steps.

To follow up, the results were analyzed visually one by one to ascertain whether the

macrolide fulfilled the desired characteristics. Because of the fact that the search was made

twice using different strategies, some results were duplicated and it was necessary to reject

those. Finally, a table was generated to organize the data.

Scheme 3. Template used to search by reaction.



6. RESULTS AND DISCUSSION

After searching (for the period 2012–2017) for the total synthesis of macrolides published in

the literature (as discussed in the Methods Section), the data was organized into tables (Tables

1-3). Tables 1 and 2 show the results of macrolactonization and RCM respectively, whereas

Table 3 shows all the results of the alternative methods of cyclization. As observed in Figure 2,

once the results are analyzed, we can confirm that the most used methods to cyclize the

macrolide ring are macrolactonization, RCM and an alternative RCM method: ring-closing

alkyne metathesis (RCAM). However, we can also conclude that coupling methods, such as the

Stille, Heck or Suzuki couplings, are also frequently used, while methods that involve the

formation of a double bond to close the ring, such as the Horner–Wadsworth–Emmons (HWE)

or Wittig reactions, are less used. Finally, cyclizations using other methods are scarce.

Figure 2. Methods of macrolide ring formation (2017–2012).


Figure 3 shows the number and type of cyclizations per year. As can be seen, the use of

alternative methods has increased in the last years. However, macrolactonization and RCM

remain the preferred methods to construct the ring of macrolides.

Figure 3. Methods of macrolide ring formation.

Particularly, a peak in the use of RCAM between the years 2013 and 2015 is observed. This

can be attributed to the studies performed by Alois Fürstner, who has developed this method for

the total synthesis of natural products. In addition, the use of cross couplings (Stille, Heck and

Suzuki) and methods that form double bonds (Wittig and HWE) has increased in the last years.

However, no Negishi cross coupling was found for the ring formation of macrolides, probably

because of the difficulty of the preparation of the required organozinc compound. Another

reaction that was not found is the Julia–Kocienski reaction, despite the fact that it is commonly

used to form alkenes.

Moreover, only two of the alternative methods found forms a new stereocenter: the Nozaki–

Hiyama–Kishi coupling and reactions that involve attack of an organometal to an aldehyde.

In the next pages, we will review the most used alternative methods for macrolide ring

formation in the period 2012–2017. In addition, whenever possible, a comparison of the different


methods of ring formation (including macrolactonization and RCM) for a given compound is

made.

2017 2016 2015 2014 2013 2012

Yamaguchi: Leptolyngbyolide C10 Benzylbryostatin 10ª,11 Biselide A12 Dendrodolide L13 Shiina: Sacrolide A14 Pestalotioprolide C15 Halichondrins A-C16 Aspergillide D17 Kita-Trost: Amphidinolide E4 Keck: Polycavernosides A and B18 Others: Tylactone19

Yamaguchi: Sch-72567420 Amphidinolide Q21 (+)-Brefeldin A22 Mandelalide A and Isomandelalide A23 Shiina: Mandelalide A24 (+)-Cladospolide D25 Thuggacin A26 Koshikalide27 δ12-Prostaglandin J3

a,28 Boeckman: Several macrolide antibiotics29

Yamaguchi: (-)-A26771B30 Recifeiolide31 Enigmazole A32 Shiina: Amphidinolide K8 Paleo-soraphens33 Dictyostatin34 Boeckman: Lyngbouilloside35 (-)-Lyngbyaloside B36 MNBA: (-)-Eushearilidea,37 Others: Musky macrolactones38 Amphidinolide P39

Yamaguchi: (-)-Leiodermatolide39 Spinosyn A40 Shiina: Thuggacin B41

Yamaguchi: (+)-Neopeltolide42 (+)-Aspicilin43 Spirastrellolide A44 Amphidinolides T1, T3, T445 Lactidomycin 46 Shiina: Dictyostatin47 Mitsunobu: (+)-18-epi-Latrunculol A48 49 Others: Amphidinolide P50

Yamaguchi: Spirastrellolide A methyl ester51 Palmerolide C52 Bafilomycin A153 Epothilones B and D54 Ivorenolide A55 Amphidinolide F56 57 FD-89158 (+)-Neopeltolide59 (+)-Aspicilin60 Aspergillides A and B61 (-)-Exiguolide62 Shiina: (-)-Hybridalactone63 Halichondrin C64 65 Kita: Amphidinolide W66

(a) Analog or derivative synthesis

Table 1. Macrolides prepared by macrolactonization in the period 2012–2017.

2017 2016 2015 2014 2013 2012

(+)-Methynolide67 Salinomycina,68 Carolactona,69 Dodecanolides70 Epothilonesa,71 Bryostatins72

Leiodolide A73 Dendrodolide-L74 (-)-Lyngbyaloside B75 C-4-epi-Sch72567476 Gliomasolide C20 Sch72567476,77 Tetradecen-13-olidea,78 Sporiolide B79 2,11-Cembranoid80

Desmethylerythromycina,81 Tiacumicin B82 Mycalolides A and B83 Pestalotioprolide A84 Lyngbyaloside C85 Ipomoeassin F86–89 Paleo-soraphens33 (-)-Exiguolide90,91 (+)-Neopeltolide92 Migrastatin and Isomigrastatin 93 Cytochalasin B94 Amphidinolide P95

FD-89196 Ivorenolide B97 Iriomoteolide 3a98 Sekothrixide99 Amphidinolide Ya,7 Sch725674100,101 aspergillide Ba,102 Carbohydrate-fused macrocycles103 Aspicillin104 Pectenotoxin-2105 Ripostatina,106 Carolacton107 Dendrodolide A108 109 Dihydroecklonialactone B110

Epothilone D111 6-Deoxyerythronolide B112 13-Demethyllyngbyaloside B113 (-)-Amphidinolide O114 (-)-amphidinolide P114 (+)-Neopeltolide and 8,9-Dehydroneopeltolide115 Yuzu lactone, Ambrettolide and Epothilone C116 Aspergillides A, B and C117 Pladienolide B118 Bafilomycin119 Lyngbyaloside B120 Carolacton121 Tulearin C122 Soraphen Aa,123

Balticolid124 Pikromycin125 6-hydroxy-12-methyl-1-oxacyclododecane-2,5-dione126 (-)-Zampanolide127 Palmerolide A128 Dihydrocineromycine B129 Ripostatin B130–133 Ripostatin A134 Iriomoteolide 1a135 FD-895136 Amphidinolactone A137 Amphidinolides B, G, and H138 Gephyromantolide A139 (+)-Neopeltolide core140 (+)-Aspicilin141 Isomigrastatin142 Aspergillide A61 4,8-Didesmethyl telithromycin143


Table 2. Macrolides prepared by RCM in the period 2012–2017.

2017 2016 2015 2014 2013 2012

RCAM

(+)-Aspicilin144

Enigmazole A145 Ivorenolide A146

Tulearin A and C147 Dihydrocineromycin B148,149 Brefeldin A150 Ivorenolide B151 Brefeldin A150

Mandelalide A152,153 Leiodermatolide154 Cucujolide V155,156

Lactimidomycin and Isomigrastatin157 Amphidinolide F158,159 WF-1360F160 Polycavernoside A161 A26771B162

Leiodermatolide163

Stille coupling Biselyngbyaside164 Chivosazole F165

Biselyngbyolide166,167 Truncated superstolide A168

Heck coupling Pestalotioprolide G169 Mandelalides A-D170

Maltepolide C171 Biselyngbyolide B172 (-)-Mandelalide A173

Palmerolide A174 Kulkenon175 Mandelalide A176

Palmerolide A177

Suzuki coupling Tiacumicin B178 Ripostatin a,106

HWE

Gliomasolide Ea,179 Neomaclafungin A180

Brefeldin A181

(-)-Marinisporolide C182,183

Mandelalide A184 Lactimidomycina,185,186 (-)-Zampanolide and (+)-Dactylolide187

Ru-catalyzed alkene– alkyne coupling

Laulimalide188

Wittig Aspicillin189 (+)-Chloriolide190

Castro–Stephens

Glaser–Hay coupling

Ivorenolide A191 Lactimidomycin192

Nozaki–Hiyama–

Kishi coupling

Sacrolide A193 Cethromycina,194

Organometal addition to an

aldehyde

Aplyronine A195 Borrelidin a,196 Epothilone D197


Table 3. Macrolides prepared by other methods (2012–2017).


6.1. MACROCYCLIZATION VIA STILLE COUPLING

The Stille coupling198 is a palladium-catalysed cross-coupling reaction that involves the

reaction of organostannanes and aryl or vinyl halides to form a new C–C bond. In 1976, the first

report of the reaction was made by Eaborn and Kosugi. However, Stille and his co-workers

transformed it into a standard method in organic synthesis. The use of the Stille coupling has

increased in the last few years and is used more and more to construct a variety of ring

systems.199–202 Its tolerance towards most functional groups made the Stille coupling an

effective reaction, displaying high selectivity.

A scheme of Stille coupling is shown in Scheme 4. An oxidative addition between Pd0 and

the vinyl halide part in the molecule forms an intermediate species that transmetallates with the

organostanne. Transmetallation is believed to be the slow step of the reaction, as the only

observable species is the vinylpalladium intermediate. Later, a reductive elimination forms the

macrolide ring.

Scheme 4. The Stille coupling to form a macrolide.

The total synthesis of natural products using a Stille reaction as the macrocyclization step

has been reviewed, although the recent literature is not covered.199–202

Truncated Superstolide A (Figure 4) was successfully synthesized using Stille coupling as

the macrocyclization step in 2013 by Jin and his co-workers.168 Superstolides A and B were

isolated in minute amounts from the deep-water marine sponge Neosiphonia superstes and

exhibit a potent antiproliferative effect against several tumor cell lines. Several years ago, Jin

initiated research towards the total synthesis of Superstolides A and B. Because of the

structural complexity of the target molecules, it would be extremely challenging to develop a


practical synthesis that provides adequate amounts. Therefore they decided to develop first a

practical total synthesis of an analog.

Figure 4. Superstolide A, Superstolide B and truncated Superstolide A.

Considering the drawbacks of macrolactonization in the previous studies, they used the

Stille coupling to form the ring. The Stille macrocyclization of truncated Superstolide A was

achieved in excellent yield (88%), using the conditions developed by Farina in 1991203 (Sheme

5).

Scheme 5. Cyclization step to form truncated superstolide A.

In 2014, the research group of Suenaga achieved the first total synthesis of Biselyngbyolide

A,166 an 18-membered marine macrolide with significant biological activities. Using a similar

approach, they published the total synthesis of Biselyngbyolide B167 in 2016 and of

Biselyngbyaside in 2017164 (Figure 5).

Figure 5. Biselyngbyolide A, Biselyngbyolide B and Biselyngbyaside.


In all of these syntheses, they build the ring using the Stille coupling (Scheme 6). The first

intention was to form the ring using macrolactonization, but they could not obtain the

hydroxyacid precursor because the conjugated diene was unstable under the oxidation reaction

conditions. In the three cases, the yield achieved was 53%, 94% and 81% respectively.

Scheme 6. Cyclization step to obtain protected Biselyngbyolide A.

Chivosazole F was synthesised by the Paterson research group in 2017.165 They first

wanted to use a Horner–Wadsworth–Emmons reaction to form the C2–C3 bond of the

macrolide. This would avoid manipulating a vulnerable (Z,E,Z,E)-tetraenoate motif. However,

the required aldehyde could not be prepared because of the instability of the precursor. The

researchers chose a Stille coupling as an alternative. Finally, the cyclization of Chivosazole F

was achieved in 41% of yield (three steps) (Scheme 7).

Scheme 7. Cyclization step to form Chivosazole F.


6.2. MACROCYCLIZATION VIA HECK COUPLING

The Heck coupling204 is a palladium-catalyzed cross-coupling reaction between an aryl or

vinyl halide with an alkene in the presence of a base which results in the formation of a C–C

bond. The Heck coupling is also called Mizoroki–Heck reaction as the result of the

investigations that Mizoroki and Heck made independently. However, Heck developed the

general method that is used nowadays. Although small variations of substrates or ligands can

change dramatically the results of the reaction, the Heck reaction is one of the most versatile

reactions in the synthesis of natural products.

In Scheme 8 we can see the construction of a macrolide using the Heck coupling. In most

cases, Pd0 is prepared from palladium complexes by reduction. An oxidative addition is required

to insert palladium in the aryl or vinyl halide bond. In the following step, the alkene coordinates

with Pd and a migratory insertion follows. Finally, a reductive elimination forms the ring of the

macrolide. The first Heck coupling used in the total synthesis of a macrolide was reported by

Zeigler and co-workers in 1981 in their total synthesis of carbomycin B.205 Since then many

research groups have used the Heck coupling as the macrocyclization step, and the recent

literature has been reviewed.199

Scheme 8. The Heck coupling to form a macrolide.


Palmerolide A was prepared by the research groups of Dudley177 and Mohapatra,174 using a

similar Heck macrocyclization (Scheme 9). Furthermore, Palmerolide A has also been

synthesized using RCM by Prasad in 2012.128 The cyclization yield was 62% and Grubbs

second generation catalyst was used (Scheme 10). Scheme 11 shows the structure of

Palmerolide A and a comparative between the different macrocyclization methods used.

Scheme 9. Cyclization step using the Heck coupling to form protected Palmerolide A.174

Scheme 10. Cyclization step using RCM to form protected Palmerolide A.128

Scheme 11. Palmerolide A: comparison of methods used for formation of the ring.

In 2014, Kulkenon was prepared by Kalesse.175 A Heck macrocylization, followed by

deprotection, permitted the synthesis of Kulkenon in 25% yield for the two steps (Scheme 12).

The Heck reaction afforded an inseparable mixture of isomers that could only be separated after

deprotection of the two TBS groups. The authors offer no explanation as to the identity of the

isomers formed during the cyclization. This represents the first total synthesis of Kulkenon and

permitted the assignment of the correct configuration of this interesting natural product.


Scheme 12. Last steps in the total synthesis of Kulkenon.

Mandelalide A was also prepared using an intramolecular Heck reaction by two different

research groups in 2014 and 2016 (Scheme 13). Gosh and co-workers achieved a 58% yield in

the Heck macrocyclization step.176 This allowed them to complete the total synthesis of

Mandelalide A aglycone. The research group of Smith prepared the natural product macrolide

using similar conditions achieving a 75% yield in this step.173 They applied the same approach

to the synthesis of Mandelalide L, an analog of Mandelalide A.

Scheme 13. Cyclization step to form the proposed structure of Mandelalide A aglycone.176

In addition, Mandelalide A was also synthesised using a macrolactonization in 2016 by two

research groups. Ghosh and his co-workers used a Yamaguchi macrolactonization to achieve

the protected macrolide in 56% yield.23 Altmann’s research group tried to employ Yamaguchi,

Keck and Corey–Nicolaou macrolactonization protocols but they only obtained traces of

Mandelalide A. Fortunately, the Shiina conditions allowed them to obtain a 57% yield in the

cyclization step using high-dilution conditions with 4-fold excess of MNBA and 10-fold excess of

DMAP.24 However, the double bond conjugated to the carboxylic acid group partially migrated to

the , position and an isomerization step was needed. Moreover, Mandelalide A was also

cyclized using a HWE reaction,184 as explained in section 6.5 and a RCAM152,153 (Scheme 14).


Scheme 14. Mandelalide A: comparison of methods used for formation of the ring.

Biselyngbyolide B was also macrocyclized using a Heck reaction in 2016 by Goswami.172

They studied the optimum reagents needed for this transformation and discovered that a

combination of Pd(OAc)2/K2CO3/Bu4NCl in DMF afforded the desired macrocycle in 58% yield

(Scheme 15).

Scheme 15. Cyclization step to form protected Biselyngbyolide B.

The same year Ghosh prepared Maltepolide C, a macrolide that was first isolated from the

fermentation broth of the Myxobacterium Sorangium Cellulosum (Figure 6).171 The

macrocyclization was achieved in 55% yield over two steps (Scheme 16).

Figure 6. Structure of Maltepolide C.


Scheme 16. Cyclization step to form protected Maltepolide C.

Pestalotioprolide G was synthesized in 2017 by Goswami.169 The authors chose a Heck

macrocyclization, instead of the more common macrolactonization approaches for two reasons.

First, the synthetic route would be more convergent, and second, it would avoid the difficult

synthesis of the acid functionality at C1 from its corresponding alcohol in presence of a sensitive

diene moiety. After screening a number of reaction conditions, they only achieved a 25% yield in

the cyclization. They attributed this low yield to the ring strain which was expected to develop

during the installation of the diene moiety. This is the first report of the construction of such a

14-membered ring system using a Heck macrocyclization (Scheme 17).

Scheme 17. Cyclization step to form Pestalotioprolide G.

6.3. MACROCYCLIZATION VIA SUZUKI COUPLING

The Suzuki coupling206 is a palladium-catalyzed cross-coupling reaction where an

organoborane and a vinyl or aryl halide react to give the coupled product under basic

conditions. This reaction is also called Suzuki–Miyaura coupling, recognizing the efforts of both

Miyaura and Suzuki in developing the method. However, the reaction is well-known as Suzuki

coupling. The method provides a good versatile solution to construct a new C–C bond with a

high tolerance of many functional groups. In addition, the stability to air and moisture of the

organoboranes involved has turned the reaction into one of the most used cross-couplings in

organic chemistry.


The catalytic cycle of the Suzuki coupling is shown in Scheme 18. To begin with, an

oxidative addition between the vinyl or aryl halide and palladium takes place. The presence of a

base gives an intermediate that allows the transmetallation to occur, obtaining a species that is

transformed into the macrolide by reductive elimination. The first Suzuki macrocyclization used

in the total synthesis of a macrolide was White’s total synthesis of rutamycin in 1998.207 Since

then many examples have appeared in the literature,199 although only two in the period

examined.

Scheme 18. Proposed catalytic cycle of the Suzuki coupling to form a macrolide.

In 2014, Prusov and co-workers synthesized 5,6-dihydroripostatin A, a Ripostatin analog, in

26% yield using an intramolecular Suzuki reaction (Scheme 19).106 In view of the poor yield

obtained, they tried to use a macrolactonization but were not able to prepare the required seco-

acid. An alternative Suzuki macrocyclization also failed. Fluorinated analogues were then

prepared using RCM, as in a previous total syntheses,130–133 obtaining, in this case, good yields

(Scheme 20).

Scheme 19. Cyclization step to form protected 5,6-dihydroripostatin A.


Scheme 20. Ripostatin B: comparison of methods used for formation of the ring.

The aglycone of Tiacumicin B, also called lipiarmycin A3 or fidaxomicin, is an atypical

macrolide antibiotic used in the treatment of Clostridium difficile infections. Its total synthesis

was reported by Glaus and Altmann in 2015 for the first time.178 The ring closure was effected

using [Pd(PPh3)4], TIOEt and was complete in less than 30 minutes at room temperature

obtaining a 73% yield (Scheme 21). In addition, Tiacuminicin B was also synthesised the same

year using RCM in the macrocylization step by Elias Kaufmann and his co-workers.82 Using the

second generation Grubbs catalyst (20 mol %) a 75% yield was obtained, although as a 2:1 E:Z

mixture. The Z alkene could be isomerized to the desired E compound. As a result the overall

yield for the E alkene increased to 63% (Scheme 22).

Scheme 21. Cyclization step to form protected Tiacumicin B.

Scheme 22. Tiacumicin B: comparison of methods used for formation of the ring.


6.4. MACROCYCLIZATION VIA WITTIG REACTION

The Wittig reaction208 involves the formation of a double bond between an aldehyde or a

ketone with a triphenyl phosphonium ylide, also called a Wittig reagent. In 1954, George Wittig

discovered this reaction and became a popular way to synthesize alkenes. Nowadays, it is also

used to form the ring in organic macrocycles. The Wittig reaction is compatible with most of the

functional groups but if the aldehyde or ketone is sterically hindered, the reaction may be slow

and give poor yields.

In Scheme 23, the Wittig reaction in its intramolecular version to form a macrolide is shown.

First, nucleophilic addition of the Wittig reagent to the carbonyl gives an intermediate betaine. A

carbon-carbon bond rotation of this betaine forms an oxaphosphetane that eliminates

triphenylphosphine oxide to form the macrolide ring.

Scheme 23. Wittig reaction to form a macrolide.

During the period examined only two total syntheses of macrolides using a Wittig

macrocyclization have appeared in the literature, both by the group of Schobert. In 2014, they

prepared Chloriolide190 as shown in Scheme 24. The air- and moisture-stable ylide is prepared

by reaction of an alcohol with Ph3PCCO. Then, they unmask the hemiacetal by acid treatment,

a process that converts the ylide into the corresponding phosphonium salt. The ylide is then

regenerated with NaOH and reacts in situ with the aldehyde in equilibrium with the hemiketal,

forming the desired E-alkene in 65% yield.

Scheme 24. Cyclization step to form Chloriolide.


The same group prepared also Aspicilin in 2017 using a similar strategy (Scheme 25).189

The reaction temperature had to be controlled to avoid a competitive intramolecular conjugate

addition between to the ,-unsaturated ester formed in the intramolecular Wittig reaction,

forming a tetrahydrofuran ring. Running the Wittig reaction at 70 ºC, suppressed the undesired

conjugate addition and provided aspicillin in 40% yield. Moreover, Aspicilin was also prepared in

2012 by Hou using RCM conditions with the second generation Grubbs catalyst in 40% yield.141

Furthermore, this macrolide has also been synthesized using a macrolatonization.60 In 2012,

Reddy used a Yamaguchi reaction to provide the protected macrolide in 68% yield (over 2

steps) (Scheme 26).

Scheme 25. Cyclization step to form protected Aspicilin.

Scheme 26. Aspicilin: comparison of methods used for formation of the ring.

6.5. MACROCYCLIZATION VIA HORNER-WADSWORTH-EMMONS REACTION

The Horner–Wadsworth–Emmons olefination (HWE) is the reaction between an aldehyde or

a ketone with a stabilized phosphonate carboanion that involves the formation of a double bond.

The HWE reaction shares some characteristics of the Wittig reaction, but as result of the more


nucleophilic and less basic properties of phosphonate-stabilized carboanions, the reaction is

milder and more likely to occur.

Scheme 27 shows a representation of the HWE reaction for the formation of macrocycles.

At the beginning, a nucleophilic addition of the carbanion to the aldehyde or ketone produces an

intermediate that converts into an oxaphosphetane. Finally, elimination of a phosphate

generates the macrocyclic alkene.

Scheme 27. HWE reaction to form a macrolide.

The intramolecular Horner-Wadsworth-Emmons reaction has been a reliable procedure for

the formation of macrolides since the pioneering studies, in 1979, of Stork and Nakamura209 and

Nicolaou.210 During the period examined several product macrolides have been cyclized using

this method.

For example, the macrocycle of Zampanolide and Dactylolide was successfully synthesized

using the HWE reaction in 2012 by Altmann in excellent yield (Scheme 28).187 The synthesis of

side chain-modified zampanolide analogs using the same approach is also described in the

paper. In addition, Zampanolide was also synthesised in 2012 using RCM by the Ghosh

research group using the Grubbs II catalyst in 65% yield127 (Scheme 29).

Scheme 28. Cyclization step to form the core macrocycle of Zampanolide and Dactylolide.


Scheme 29. Zampanolide: comparison of methods used for formation of the ring.

An intramolecular HWE reaction was also used to prepare Mandelalide A in 2014 by the

research group of Xu and Ye.184 The macrocyle was obtained in 44% yield for two steps

(Scheme 30).

Scheme 30. Cyclization step to form protected Mandelalide A.

In 2013, Nagorny published the total synthesis of Lactimidomycin using a HWE

cyclization.186 The high ring-strain of this 12-membered unsaturated macrolide complicates the

preparation of the cycle (Figure 7). The authors chose a HWE reaction to form at the same time

the ,-unsatured lactone and the ring, thus minimizing manipulation of this sensitive moiety.

After optimization, a Zn(II)-mediated HWE reaction furnished the desired macrocycle in 93%

yield. Finally, deprotection and installation of the side chain afforded the final compound

(Scheme 31).

Figure 7. Structure of Lactimidomycin.


Scheme 31. Cyclization step to form protected Lactimidomycin macrocycle.

Dias and de Lucca published in 2015 the first total synthesis of Marinisporolide C, a 34-

membered oxopolyene macrolide using an intramolecular HWE reaction.182 The authors initially

planned to synthesise Marinispolide A, which is a geometrical isomer of Marinispolide C (Figure

8). Surprisingly, after HWE macrocyclization and global deprotection, they isolated, in 15%

yield, Marisnispolide C (Scheme 32). When Marinispolide A is exposed to ambient light, an

equilibrium mixture favoring Marisnispolide C is obtained after 2 h. This seems to indicate that

Marinispolide C is the thermodynamically most stable isomer. As the authors conducted their

reactions in the dark, they believe that Marinispolide C was formed due to acid-catalyzed

isomerization. Two years later, in 2017, a full report of this total synthesis was published.183 In

this second article, the authors describe that attempts at the total synthesis of the Marinispolides

using several macrolactonization protocols were unsuccessful, probably due to the presence of

an -substituent in the ,-unsaturated seco-acid.

Figure 8. Structures of Marinisporolide A and C.

Scheme 32. Cyclization step to form protected Marinisporolide C.


Brefeldin A was synthesized in 2016 by Raghavan and Yelleni.181 They used the Roush–

Masamune conditions (LiBr, DBU and Et3N) to form the ring in 60% yield (Scheme 33). Finally,

deprotection of the silyl ethers under acid conditions furnished the final compound. An

alternative synthesis of Brefeldin A using a Yamaguchi macrolactonization was also described

in 2016 by Hale in 80% yield22 (Scheme 34).

Scheme 33. Cyclization step to form protected Brefeldin A.

Scheme 34. Brefeldin A: comparison of methods used for formation of the ring.

Two diasteromers of Gliomasolide E were prepared in 2017 by the group of Mohapatra.179

They also used the Roush–Masamune conditions obtaining a 80% yield in the HWE cyclization

(Scheme 35). By comparison of the NMR data of the two Gliomasolide E diasteromers with that

of the natural product, they could assign the absolute stereochemistry of the natural product.

Scheme 35. Cyclization step to form two protected diasteromers of Gliomasolide E.


In 2017, the total synthesis of Neomaclafungin A was published by Wu.180 The formation of

the ring of this complex molecule worked in only 33% yield (Scheme 36). Nevertheless, after a

difficult final global deprotection, they could complete the synthesis of the macrolide and

establish its relative and absolute configuration.

Scheme 36. Structure and cyclization step to form Neomaclafungin A.



7. CONCLUSIONS

In this work, a bibliographic search has been undertaken to find which macrocyclization

methods, apart from macrolactonization and ring-closing metathesis, are used nowadays for the

synthesis of macrolides. Many methods have been identified and five of them have been

reviewed. Three of these methods were cross-coupling methods and the other two were based

on the formation of a double bond.

Analysis of the number of articles per method, we can conclude, as expected, that

macrolactonization and RCM are still preferred to cyclize macrolides. However, a growth in the

use of alternative methods is observed, especially for RCAM. Cross-coupling methods are also

gaining popularity for macrocyclization. Ring-closure of the cycle by formation of a double bond

(Wittig and HWE) is less used.

The literature review reveals that it is not straightforward to predict the best approach to

cyclize a particular structure. Without doubt, macrolactonization is the most general strategy but,

even though there are many different conditions for this reaction, sometimes a particular

substrate will not macrolactonize successfully (because of ring strain, instability of the

substrate...). In these instances, RCM approaches are probably the best alternative if the

macrolide has a suitable structure. For macrolides with 1,3-dienes, Heck, Suzuki or Stille cross-

couplings can also be used with some confidence. Despite all the benefits that

macrolactonization and RCM have, alternative methods can be beneficial in some cases, as the

literature review attests, and afford, in some cases, the same or better yields than classical

macrolactonization or RCM approaches.


Bibliographic review of alternative macrocyclization methods for the synthesis of macrolides 41

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9. ACRONYMS

Ac Acetyl

Bpin “Boron pinacolate”

dba Dibenzylideneacetone

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DIPEA N,N-Diisopropylethylamine

DMF N,N-Dimethylformamide

HMDS Hexamethyldisilazane

HWE Horner-Wadsworth-Emmons

MNBA 2-methyl-6-nitrobenzoic anhydride

MOM Methoxymethyl

NMR Nuclear Magnetic Resonance

OAc Acetoxy

OTf Triflate

PMB p-Methoxybenzyl

PMP p-Methoxyphenyl

py Pyridine

RCAM Ring-closing alkyne metathesis

RCM Ring-closing metathesis

TAS-F Tris(dimethylamino)sulfonium difluorotrimethylsilicate

TBDPS tert-Butyldiphenylsilyl

TBS tert-Butyldimethylsilyl

TC Thiophene-2-carboxylate

TEMPO 2,2,6,6-Tetramethylpiperidin-1-oxyl

TES Triethylsilane

THF Tetrahydrofuran

TMEDA Tetramethylethylenediamine

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Treball Final de Grau - UBdiposit.ub.edu/dspace/bitstream/2445/124728/1/TFG... · compounds have been found, particularly in drug discovery. For instance, Erythromycin A and ... controlling